delta-allopregnene derivatives



United States Patent Ofifice 3,056,814 Patented Oct. 2, 1962 3,056,814 M-ALLOPREGNENE DERIVATIVES Albert Bowers and John Edwards, Mexico City, Mexico,

assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Nov. 2, 1961, Ser. No. 149,502 Claims. (Cl. 260-39145) CHzOR In the above formula X represents Y represents hydrogen, fluorine or chlorine; Z represents hydrogen, fluorine, chlorine or methyl; R represents hydrogen, a-methyl, fl-methyl, a-hydroxy or a-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

The acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and p-chloropropionate.

The novel compounds of the present invention are prepared by the process illustrated by the following equation:

ooH O-OH;

1--. o 0 HO R HO R Br- I Ba HO o- 2 IV III OHQORI CHzOR I {1:0 "-OH '"OH no-pl 1MB HO lj TWR EPA k/ i v VI CHzOR onion 5:0 5:0

"-011 "*OH HO M R NW R I ll Br/ Br-- BI-K/; 3Tb.

. z VIII VII CHzOR "'OH HO- M R I l i i i i IX In the above formulas, R, R and Z have the same meaning previously set forth; W represents fluorine or chlorine.

In practicing the process outlined above, the starting compound which is a hydrocortisone derivative (1) is treated conventionally with formaldehyde to give the corresponding 17,20;20,2l-bismethylenedioxy derivative. Hydrogenation of the latter compound with, for example, hydrogen and a suitable catalyst such as 5% palladium on charcoal, followed by chromatographic separation affords the corresponding pregnane derivative and the corresponding allopregnane derivative (II). The last named com-pound, upon bromination with 1.1 mol equivalents of bromine in the presence of hydrogen bromide, furnishes the corresponding 2a-bI'OIIl0-3-k6t0 derivative (III). Reduction of the 3-keto group of this compound preferably with sodium borohydride yields of B S-hydroxy derivative (IV) which upon treatment with a suitable reagent such as chromous chloride solution, affords the respective A -allopregnene derivative. The 17,20;20, ZI-bismethylenedioxy group of the last named compound is conventionally hydrolyzed in an acid medium, such as 80% acetic acid to give the corresponding A -allopregnene-17a,21-diol-20-one derivative The 160:- and/or 21-hydroxyl groups present in the molecule of this latter derivative, are conventionally acylated in pyridine with an acylating agent, preferably acetic anhydride to give the corresponding 16a,2ldiester or 21-monoester A -allpregnene derivative Addition of bromine to the A -double bond afford the respective 23,3a-dibromo-allopregnane compound (VI: R =acyl).

A double bond is introduced between 09 and GM of the molecule of the last named compound by dehydration with mesyl chloride in dimethylformamide, thus obtaining the corresponding 2a,3a-dibromo-A -allopregnene derivative (VII: R =acyl). Treatment of this compound with a bromoamide such as N-bromoacetamide in the presence of a mild acid, preferably perchloric acid, in a suitable solvent such as dioxane, furnishes the corresponding 9a-bromo-1lfi-hydroxy-allopregnane derivative which upon reaction with a mild base, preferably potassium acetate affords the respective 96,11fi-oxidoallopregnane compound. The opening of the 9 6,115- oxide ring with hydrogen fluoride or hydrogen chloride leads to the formation of the corresponding 9a-fiuoro or 9a-chloro-ll 8-hydroxy compound (VIII: R =acyl). Debromination of this compound with a suitable agent such as sodium iodide in methyl ethyl ketone, affords the respective A -allopregnene derivative (IX: R =acyl). Oxidation of the 1lfi-hydroxy-n -allopregnene derivative (V: R =acy1) and the 9a-halo-llfl-hydroxy-n -allopregnene derivative (IX: R =acyl) furnishes the corresponding ll-keto compound.

Conventional saponification of the l6a,2l-diester or 2l-monoester derivatives of the llfi-hydroxy compounds (V: R =acyl and IX: R =acyl) and of the corresponding ll-keto compounds affords the corresponding A -allopregnene-ll,B,l7a,2l-triol-20-one derivatives (V: R ==H and IX: R =H) and A -allopregnene-17a,21-diol-3,11,20- trione derivatives.

Conventional acylation of these free alcohols in pyridine with an acylating agent such as an anhydride of a hydrocarbon carboxylic acid of the type defined hereinbefore, furnishes the corresponding acylates which may be different from the esters preceding the saponification.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I A solution of 6 g. of 6a,l6 8-dimethyl-A -pregnen-11B, l7a,21-triol-3,20-dione (Djerassi, US. Patent Application Serial No. 796,766 filed March 3, 1959) in 50' cc. of 37% aqueous formaldehyde was treated with 0.5 cc. of concentrated hydrochloric acid and the mixtures stirred for 48 hours at room temperature. It was then poured into water, the formed precipitate filtered off, washed with water to neutral and dried under vacuum thus affording 6a,16,3-dirnethyl-17,20;20,21 bisrnethylenedioxyN-pregnen-11fl-o1-3-one.

. When applying the above described procedure to the starting compounds listed below, there were obtained the corresponding products hereinafter set forth:

Starting compounds Products (Djerassi et a1, copending application Serial No. 825,665 filed July 8, 1959.)

16/3-rnethyl-Sn-fiuoroh -pregnene- 116,170,21-tri0l-3,20-dione.

(Djerassi, copending application Serial No. 792,962 filed February 13, 1959.)

fia-fiuoro-A preg'nene- 11B, 16a, 17a,-

2l-tetrol-3,20-dione.

Ga'ChIOIOhYdIOCOItiSOHG Hydrocortisone l6a-methy1-6a-fiu0ro-17,20;20,21-

bismethylenedioxy-N-pregnen- 116-01-3-one.

IGa-methyl-fia-chloro-17.20;20,21-

bismethylenedioxy-A -pregnen- 11Bol-3one.

61-fluoro-17,20;20,2l'

bismethylenedioxy-N-pregnene- 11B, 16a-dio1-3-one. 6a-chlot0'17,20;20,21-

bismethylenedioxy-A -pregnene- 115,16wdi0l-3-one. 6a-chloro-17,20;20,21-

bismethylenedioxy-A -pregnene- 11fl-ol-3one. 17,20;20,21-bismethylenedioxy- A -pregnene-l 1,301-3-0ne.

Example 11 6 g. of 6a,16,8-dimethyl-17,20;20-2l-bismethylenedioxy- 20;20,21-bismethylenedioxy-allopregnan-1 l /3ol-3-one.

The starting compounds listed below were treated following the above procedure, thus furnishing the corresponding products hereinafter set forth:

Starting compounds Products 1(ia methy1-6a-chloro-17,20;20,21-

bisrnethylenedioxy-N-pregnen- 11fl-ol-3-one.

6a-eh1oro-17,20;20,21-bismethylenedioxy-A -pregnene-llfldoadiol-3-one.

fia-chlOro-IZZO;20,21-bismethylenedloxy-A -pregnen-llflpl-iione.

17,20;20,21-bismethy1enedioxy- A -pregnen-11fi-ol-3-one.

. one. 6a-chloro-17,20;20,2l'bismethylenedioxy-allopregnane-l1,5,

di0l-3one. 6a-ehlor0-17,20;20,21-bismethylenedioxy-pregnan-l1fl0l-3-one. Goa-chloro-l7.20;20,21-bismethylenedioxy-allopregnan-llB-olhone.

17,20720,21-bismethy1enedioxypregnan-11flol-3-one.

17,20 ;20,2l-bismethylenedioxyal1opregnan-1lfl-ol-3-one.

Example III A solution of 5 g. of 6a,16fi-dimethyl-l7,20;29,2l-bismethylenedioXy-allopregnan-ll,B-o1-3-one in cc. of acetic acid was treated with a few drops of hydrogen bromide in acetic acid and subsequently dropwise and under stirring with a solution of 1.1 molar equivalents of bromine in 50 cc. of acetic acid. After all the bromine sponding products hereinafter set forth:

Starting compounds Products 17 ,20;20,21-bismethylenedioxy-allopregnandlfi-ol-3-one.

Example IV A solution of 3 g. of sodium borohydride in 9 cc. of water was added to an ice-cooled solution of S g. of 6a,l6fl-dimethyl Za-bromo l7,20;20,21 bismethylenedioxy-allopregnan-l1,8-01-3-one, in 120 cc. of methanol and the mixture was allowed to stand for 16 hours at room temperature. The excess reagent was decomposed by addition of acetic acid, the solution concentrated to small volume in vacuo and diluted with water. The product was extracted with ethyl acetate, the extract was washed with water, dried and evaporated. The solid residue was purified by crystallization from acetone-hexane to give 6a,16fl-dimethyl-2a-bromo-17,20;20,2l-bismethylenedioxy-allopregnan-3 p, 1 1 B-diol.

The starting compounds listed below were treated by the above described technique furnishing the corresponding products disclosed hereinafter:

Starting compounds Products 1611 -methyl 2a -bromo 6oz -fluoro 17 ,20;20,21 bismethylcnedioxy allopre gnan-llB-ol-Bpnc.

16oz -rr.ethyl 2a bronco -6rz chloro 17.202021 bismethylenedioxy allo pregnan-llB-ol-Scue.

16B methyl 20: down 0 6a -fiuoro 17,20;20,21 bismethylcnedioxy allopregnan-llfi-ol-Elcne.

2u-bromo-6a-chl0ro-17,20 ;20,21-bismothylenedioXy-allopregnane- 1lB,16a-diol-3-one.

2a-brouio-6a-chlor0-17,20;20,21-bismethylene dio xy-allopregnanllflcLS-one.

16a -methyl 2oz -bro1ro Ga -fiuoro 17,20;20,21 bismethylenedioxy allopregnan-3;S,11B-diol.

16a -1rethyl 2a -bro1ro -6achloro 17 ,20;20,21 bisir ethylenedioxy allopre gnan-BBJIfl-diol.

16B methyl -2a hron o 6v: -fiuoro l7,20;20,21 bisrr ethylenedioxy allopregnane-35,11fi-diol.

2a-brorr o-Ea-fluoro-17,20;20,21-bisrr ethylcnedioxy-allopregnane- 36,115,1Ea-triol.

211-1010111047 ,20;20,21-bism ethylenedioxyallopregnane-3fi,llfl-dlol.

Example V Starting compounds Products 16a-ruethy1-6a-fluoro-17,20;20,21-bismethylenedloxy-A -allopregnen- 6a-chloro-17,20;20,21-bismethyleuedioxy-A -allopreg'nene-llfi,16a-

diol. 6u-ohloro-17 ,20;20,21-bismethylenedioxy-A -allopregnen-llB-ol.

17 ,20;20,21-bismethylenedioxy-A allopreg'nen-llflcl.

Example VI 1 g. of 6a,lofl-dirnethyl-17,20;20,2l-bismethylenedioxy- M-allopregnen-llB-ol was heated on the steam bath with 100 cc. of 80% acetic acid under nitrogen for 2 hours,

' it was then concentrated under vacuum to a small volume and poured into water. The precipitate was collected, washed well with water, dried and recrystallized from acetone-hexane, thus furnishing 6a,16,8-dimethyl-A -allopregnene-l1B,17a,21-triol-20-0ne.

When applying the above procedure to the starting compounds listed below, there were obtained the products hereinafter set forth:

Starting compounds Products fia-chlhro-HJO;20,21-bismethylene- 211ioiry-A allopregnene-Hfl,16a-

1O 6a-chloro-17,20;20,2l-blsmethylenedioxy-N-allopregnen-l15-01. 17,20;20,2l-bisrnethyleuedioxy-N- 1GB-methyI-Ga-fluoro-A -allopregnone-11B,17a,21-triol-20-one.

fia-fluoro-A -allopreguene-115,1611,

17a,21-tetrol-20-one.

6a-chloro-M-allopregnene-l15,1612,

17a,21-tetrol-20-oue.

6wohloro-A -allopreguene-ll5,1701,

21-trlo1-20-one. N-allopregnene-HBJ7a,21-triol-20- one Example VII Starting compounds Products 1(id-methyl-tia-fluoro-A -allopreg- Ilene-11B,17a,2l-triol-20-one.

fia-chloro-A -allopreguene-1113,1611,

17a,21-tetrol-20-one.

tate. 6a-chloro-A -allopregneue-11B,ltia, 17a,21-tetrol-20-one-16,21-diacetats. 6a-chloro-M-allopregnene-ll5,17

21-triol-20-one-21-acetate. N-allopregneue-l1B,17a,21-triol-20- One-ZI-acetate.

7 T Example VIII A solution of 4 g. of 6oz,16/3-dimethyLM-allopregnene- 11,8,17a,21-triol-20-one-2l-acetate obtained in accordance with Example VII in 100 cc. of chloroform containing a few drops of pyridine was cooled to C. and slowly treated under stirring with a cooled solution of bromine in chloroform containing 1.05 molar equivalents of bromine. The mixture was allowed to reach room temperature, washed with aqueous sodium bicarbonate solution and subsequently with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from methanol-benzene afforded 60c, 16;? dimethyl 25,30: dibromo allopregnane 115,170, 21-triol-20-one-2l-acetate.

Following the above technique, there was treated the starting compounds listed below, furnishing the corresponding products hereinafter disclosed:

Starting compounds Products 16a-methyl-fia-fiuoro-A -allopreg- Ilene-11,6,17a,21-trio1-20-one-21- acetate.

acetate. 1GB-methyl-fia-fluoro-N-allopregnone-11B,17a,21-tri01-20-0ne-21- acetate. Gu-fiuoro-N-allopregnene-l13,1601, 11:71%:,21 tetrol-20-orre-16,21-diacee. fia-chloro-N-allopregnene-116,1604, t1;71g,21-tetr0l-20-one-16,2l-diacea e. 6a chloro-A -allopregnene-l15,1701,

21-triol-20-one-2l-acetate.

A -allopregnene-l1B,17a,21-triol-20- one-21-aeetate.

Example X 2.8 g. of N-bromoacetamide were added to a mixture of 5 g. of 6a,16,8-dimethyl-2,8,3u-dibromo-A -allopregnene-17a,2l-diol-20-one-2l-acetate, 50 cc. of pure dioxane and 0.8 cc, of 0.4 N perchloric acid while stirring in the dark and at room temperature during 1 hour. The reaction mixture was stirred for 1 hour further, a solution of 10% sodium sulfite was then added until the potassium-starch indicator paper no longer turned blue, ice was added, the mixture was extracted with chloroform and the extract was washed consecutively with water, 5% aqueous sodium bicarbonate solution and water, and the solvent was removed by distillation under vacuo. By trituration of the residue with acetone, there was obtained the corresponding 9a-bromo-1lfl-hydroxy-allopregnane derrvatrve.

A mixture of 2 g. of anhydrous potassium acetate and 20 cc. of acetone was heated almost to boiling and then a solution of 1.7 g. of the above bromohydrin in 20 cc. of acetone was added slowly while stirring; the mixture was then refluxed for 10 hours; cooled, and almost all of the acetone was distilled off; iced water was then added, the precipitate was filtered, washed with water and dried. Upon recrystallization from methylene chloride-benzene, there was obtained 6a,16,8-dirnethyl-2B,3dibromo-9,8, 1lfi-oxido-allopregnane-17a,21-diol-20-one-21-acetate.

When applying the above technique to the starting compounds listed below, there were obtained the products hereinafter disclosed Products Example IX 5 g. of 6a,16,8-dimethyl-2B,3a-dibromo-allopregnane- 11 8,17a,21-triol-20-one-2l-acetate was dissolved with slow heating in 60 cc. of dirnethylformamide, the mixture was cooled, 2 g. of mesyl chloride and 2.5 cc. of pyridine were added and the solution was kept at 80 C. for half an hour. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished 6a,16fl dimethyl 2}3,3u dibromo A9(11) allopregnene- 17a-21-diol-20-one-21-acetate.

The starting compounds hereinafter listed were treated following the above described procedure, thus affording Starting compounds Products 11B,17a,21-trio1-20-one-2l-acetate.

Example XI To a solution of 4 g. of 60L,16j8'dlmthYl-2[3,3OC-dlbI'OmO- 93,11B oxido allopregnane 1704,21 diol 20 one- 21-acetate in 40 cc. of redistilled chloroform, was added, over a period of 35 minutes, 30 cc. of a 0.45 N solution of dry hydrogen chloride in chloroform, under continuous stirring and maintaining the temperature around 0 C. The mixture was then stirred at 0 C. for 1 hour further, diluted with water and the chloroform layer was separated, washed with water and the chloroform layer was separated, washed with aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate and the chloroform was evaporated under reduced pressure. Crystallization of the residue gave 6a,l6B-di methyl 25,30: dibromo 9a chloro allopregnane- 11B,17a,21-triol-20-one-21-acetate.

Following the above described procedure, there were Starting compounds Products Example XII In a polyethylene flask, adapted with a magnetic stirrer, there was dissolved 1.8 g. of 6a,16,8-dimethyl-2B,3a-di- Memo-95,1l,B-oxidoallopregnane-17a,2l-diol-20-one 21- acetate in 30 cc. of methylene chloride; the solution was cooled at C. and a solution of a mixture of 2.11 g. of anhydrous hydrofluoric acid and 3.7 g. of tetrahydrofuran cooled in a Dry-Ice acetone bath (7O C.) while stirring, was added during a period of 20 minutes. The mixture was stirred at less than 10 C. for 6 additional hours, was neutralized by cautiously adding a aqueous sodium bicarbonate solution, was then transferred to a separatory funnel, and the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated until formation of an abundant precipitate. The mixture was cooled, the precipitate was filtered and redissolved in hot ethyl acetate, the hot insoluble material was filtered and the filtrate cooled whereby 60:,1613- dimethyl-2fi,3a-dibromo-9a-fluoro-allopregnane 115,17a, 2l-triol-20-one-2l-acetate crystallized.

Following the above described procedure, there were treated the hereinafter indicated starting compounds, furnishing the products disclosed below.

Starting compounds Products Example XIII 10 Upon treatment by the same procedure of the starting compounds listed below, there were obtained the corresponding products hereinafter disclosed:

Starting compounds Products 16a methyl 6a fiuoro 9a chloro- N-allopregnene-llfl, 17a, 21-triol- 20-one-21-acetate.

lfia-methyl-Ga, ga-dichloro-N-allopregnene-llfl, 17a, 21-tr1ol-20-one- 21-acetate.

fia-fiuoro-tlu-chloro- A -alloprenene- 11,8, 17a, 21-tetrol-20one-16, 21-diacet-ate.

6a, Qa-dichloro-A -allopregnene- 11,8, 160:, 17a, 2l-tetrol-20-one-16, 21 diacetate.

6a, 9a-dichloro-N-allopregnene-Hfl, 17a, 21-triol20-one-21-acetate.

gwchloro-A-allopregnene-11B, 17a,

21-triol-20one-2l-acetate.

Example XIV A solution of 3 g. of 6a,l6,8-dirnethyl-9a-chloro-A allopregnene-l1 8,l7a,21-triol-20-one-21 acetate obtained acetate.

The starting materials listed below were treated following the above described procedure, affording the products hereinafter set forth:

Starting compounds Products Starting compounds Products Starting compounds Products Example XV Starting compounds Products 6a,9a-dichloro-N-alloprcgnene- 16a,17a,21-tri01-11,QO-dione.

6a,9a-dichloro-A -allopregnene- 17a,21-dio -11,20-dione.

Qa-chloro-A -allopregnene-17a,21-

dial-11,20-dione.

6a-chloro-N-allopregnene-1711,21-

diol-l1,20-dione.

A -allopregnene-fl,21-diol-11,20

dione.

6a,1Sfi-dimethyl-A -allopregnene- 17a,21-diol-11.20-dione.

6a,9a-dichloro-A -allopregnene- 11,8,17rx,21-triol-20-one.

Example XVI A mixture of l g. of 6a,16,8 dimethy1-9oc-chloro-A allopregnene-l7a,2l-diol-l1,20-dione, 4 cc. of pyridine and 2 cc. of propionic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 6a,l6fi-dimethyl-9u chloro-A -allopregnene-17a,21-diol-1 1,20-dione-21- propionate.

When applying the above procedure to the hereinafter listed starting compounds, there were obtained the respective products set forth below:

Starting compounds Products 

1. A COMPOUND OF THE FOLLOWING FORMULA: 